title: Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance.
abstract: Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target.
authors.affiliation: Authors' Affiliations: Departments of Surgery, Pathology, and Cell and Developmental Biology, Department of Internal Medicine-Gastroenterology, Michigan Center for Translational Pathology, Program in Cellular and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; Vascular Biology Program, Department of Surgery, Karp Family Research Laboratories, Children's Hospital, Boston, Massachusetts; Gastroenterology Division, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pharmacology, and University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Collins
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.forename: Sabita
authors.initials: S
authors.lastname: Rakshit
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Zetter
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Ivy
authors.initials: I
authors.lastname: Chung
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.forename: Marina Pasca
authors.initials: MP
authors.lastname: di Magliano
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation
chemical_list: D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases